With the growing social and economic impact of dementia on the society, emphasis is shifting from eariy diagnosis and treatment to prevention of cognitive impairment and dementia. The neuroprotective effects shown in animal models and cell cultures suggest that estrogen might be used in the prevention or delay of cognitive impairment and dementia in postmenopausal women. However, estrogen used as a menopausal hormone treatment (MHT) in older (i.e., not newly menopausal) women did not prevent dementia, and controversy exists about whether MHT containing estrogen can preserve neurologic function and decrease the risk of dementia when administered eariy in menopause. In this proposal, we will assess the neuroprotective effects of MHT on cognitive performance and surrogate brain imaging markers. This project leverages the existing cohort of women who participated in the Kronos Eariy Estrogen Prevention Study (KEEPS) who were treated with either oral conjugated equine estrogen ortransdremal 17(3 estradiol or with a placebo eariy in menopause, which is considered the critical window of opportunity for estrogen treatment. In addition to cognitive testing (through Core B), we will consider several imaging markers of brain. First is C-Pittsburgh Compound B (PiB) retention on positron emission tomography; this is a surrogate marker for p-amyloid pathology of Alzheimer's disease (AD). Second is the change in white-matter hyperintensity load on MRI over 7 years after randomization; this is a surrogate marker for ischemic white-matter disease. Third is change in brain volume indices on MRI over 7 years after randomization; this is a surrogate marker for neuronal degeneration. Each imaging marker should provide independent information on the common pathologic features associated with cognitive health in older adults. This project addresses an important and controversial aspect of MHT by determining whether therapy in the immediate postmenopausal years preserves cognition and neuronal integrity. Since participants will also undergo assessment of cerebral microvascular dilatory capacity and characterization of platelet and blood-borne microvesicles in Project III, insight will be gained into mechanisms which might impact progression of AD-related pathology. Collectively, findings from this study have the potential to significantly advance scientific knowledge and clinical practice by providing insight into effects of MHT on cognitive health eariy in menopause. Our findings will help patients and physicians make informed decisions regarding the benefit and risk of such treatments.